Derivatives of 1-arylsulphonyl-2-pyrrolidinone, their preparation process, intermediates thereof, their use as medicaments and compositions containing them

ABSTRACT

Compounds useful for the treatment of patients suffering from muscle spasms of the formula (I) ##STR1## in which R represents the radical ##STR2## in which R 1 , in any position on the phenyl nucleus, represents a linear, branched or cyclic alkyl, alkenyl or alkynyl, containing up to 8 carbon atoms, or the radical ##STR3## in which R 2  and R 3 , identical or different each represents a hydrogen atom, a linear alkyl, alkenyl or alkynyl, containing up to 8 carbon atoms, or form together with the nitogen atom to which they are joined, a heterocyclic radical optionally containing another heteroatom, or NO 2 , or OR&#39;, R&#39; representing hydrogen, a linear, branched or cyclic alkyl containing up to 8 carbon atoms, or aryl containing up to 14 carbon atoms, or an SR 4  or S(O)R 5  radical, R 4  and R 5  representing a linear, branched or cyclic alkyl, alkenyl or alkynyl, containing up to 8 carbon atoms, or R represents naphthyl, optionally substituted by an R 1  radical, as defined above; also therapeutic compositions containing the same and method of use.

This is a Divison of application Ser. No. 07/315,170, filed Feb. 24,1989 now U.S. Pat. No. 4,980,531, issued 2-5-91.

The present invention relates to new derivatives of1-arylsulphonyl-2-pyrrolidinone, their preparation process,intermediates thereof, their use as medicaments and the compositionscontaining them.

A subject of the invention is compounds of formula (I): ##STR4## inwhich R represents the radical ##STR5## in which R₁, in any position onthe phenyl nucleus, represents a linear, branched or cyclic alkyl, oralkenyl, or alkynyl, containing up to 8 carbon atoms, or the radical##STR6## in which R₂ and R₃, identical or different each represents ahydrogen atom, a linear alkyl, alkenyl or alkynyl, containing up to 8carbon atoms, or form together with the nitrogen atom to which they arejoined, a heterocyclic radical optionally containig another heteroatom,or NO₂, or OR', R' representing hydrogen, a linear, branched or cyclicalkyl containing up to 8 carbon atoms, or aryl containing up to 14carbon atoms, or an SR₄ or S(O)R₅ radical, R₄ and R₅ representing alinear, branched or cyclic alkyl, alkenyl or alkynyl, containing up to 8carbon atoms, or R represents naphthyl, optionally substituted by an R₁radical, as defined above.

As alkyl there is preferred an alkyl containing from 1 to 5 carbonatoms, for example, one of the following: methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl,cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As alkenyl there is preferred ethenyl, propenyl and butenyl. When R₂ andR₃ form together with the nitrogen atom to which they are joined, aheterocyclic radical optionally containing another heteroatom, there ispreferred piperidyl, piperazinyl, morpholinyl or pyrrolidinyl.

As aryl there is preferred phenyl or naphthyl.

Among the preferred compounds of the invention, there can be citedcompounds of formula (I) in which R represents the radical ##STR7## R₁having the same significance as above, and in particular those in whichthe radical R₁ is in position 4. There can also be cited compounds offormula (I) in which R₁ represents a linear or branched alkyl containingup to 8 carbon atoms and in particular tert-butyl or also those in whichR₁ represents the radical ##STR8## in which R₂ and R₃ represent linearor branched alkyl containing up to 8 carbon atoms or form together withthe nitrogen atom to which they are joined, a heterocyclic radical, oralso those in which R₁ represents SR₄, R₄ representing a linear orbranched alkyl containing up to 4 carbon atoms and in particular methyl.

Among the preferred compounds of the invention, there can be cited thecompounds, the preparation of which is given hereafter in the Examples,and quite particularly the compounds of Examples 1, 2, 3, 4 and 10.

The compounds of formula (I) show useful pharmacological properties andin particular a specific and selective anti-muscarine activity.

A subject of the invention is therefore the products of formula (I) asmedicaments, useful in particular for the anti-spasmodic treatment ofmuscle spasms in gastro-enterology, in gynaecology, in obstetrics, inurology, in hepatology and in radiology.

A subject of the invention is more particularly, as medicaments, theproducts of Examples 1, 2, 3, 4 and 10.

The usual posology is variable according to the affection in question,the patient treated and the administration route; it can be between 10mg and 1 g per day, and preferably between 20 mg and 100 mg per day, andmore particularly between 30 and 60 mg per day in one or more doses, forthe product of Example 1, administered by oral route.

A subject of the present invention is also pharmaceutical compositionscontaining as active principle at least one product of formula (I). Thepharmaceutical compositions of the invention can be solid or liquid andcan be presented in the pharmaceutical forms currently used in humanmedicine, such as for example plain or sugar-coated tablets, gelules,granules, suppositories and injectable preparations; they are preparedaccording to the usual methods.

The active principle or principles can be incorporated in the excipientsusually employed in these pharmaceutical compositions, such as talc, gumarabic, lactose, starch, magnesium stearate, cocoa butter, aqueous ornon-aqueous vehicles, fatty substances of animal or vegetable origin,paraffin derivatives, glycols, various wetting, dispersing oremulsifying agents, and preservatives.

A subject of the invention is also a preparation process for compoundsof formula (I) characterized in that 2-pyrrolidinone ##STR9## issubmitted to the action of a compound of formula (II):

    R--SO.sub.2 Hal                                            (II)

in which Hal represents chlorine or bromine, and R has the samesignificance as above, so as to obtain the corresponding compound offormula (I).

In a preferred method of carrying out the invention process, thereaction between 2-pyrrolidinone and the product of formula (II) iscarried out:

a) in the presence of a strong base such as butyllithium, an alkalihydride such as sodium hydride or sodium bis(trimethylsilyl) amide;

b) in a solvent chosen from the group constituted by tetrahydrofuran,benzene, dimethylformamide, dimethylsulphoxide, monoethyl ether ofdiethylene glycol, or diethyl ether of diethylene glycol.

A subject of the invention is also a preparation process for compoundsof formula (I), characterized in that 4-amino butyric acid is submittedto the action of a compound of formula (II):

    R--SO.sub.2 --Hal                                          (II)

in which R and Hal have the significance indicated previously so as toobtain a compound of formula (III): ##STR10## in which R has thesignificance already indicated, which is cyclized so as to obtain thecorresponding product of formula (I).

In a preferred method of carrying out the process described above:

the reaction of the 4-amino butyric acid with the compound of formula(II) is carried out in the presence of a mineral base such as sodium- orpotassium-hydroxide in an organic solvent such as tetrahydrofuran;

the cyclization of the compound of formula (III) is carried out in thepresence of a dehydration agent such as acetic anhydride, phosphoricanhydride, phosphoric acid or hexamethyldisilazane.

A subject of the invention is also the products of formula (III), asdefined previously, as new industrial products.

The following examples illustrate the invention without however limitingit.

EXAMPLE 1 1-(4-tert-butyl benzenesulphonyl)-2-pyrrolidinone

1.65 g of 2-pyrrolidinone in solution in 75 cm³ of tetrahydrofuran iscooled to -5° C., and 12.1 cm³ of a 1.6M solution of n-butyllithium inhexane is added, maintaining the temperature between -5° C. and 0° C.Agitation is carried out for 25 minutes at -5° C.; the mixture is cooledto -20° C. and 4.5 g of 4-tert-butyl-phenylsulphonyl chloride is added[Recueil Trav. Chim. Pays-Bas, 53, 1101 (1934)]. After allowing toreturn to ambient temperature, the tetrahydrofuran is evaporated offunder reduced pressure, the residue is taken up with water, filtered andcrystallized from ethanol. 2.75 g of expected product is obtained.

m.p.=131°-133° C.

Analysis: C₁₄ H₁₉ NO₃ S: 281.376; Calculated: C % 59.76, H % 6.81, N %4.98. Found: C % 59.62, H % 6.78, N % 4.79.

EXAMPLE 2 1-[4-(diethylamino)benzenesulphonyl]-2-pyrrolidinone

0.69 g of 2-pyrrolidinone in solution in 25 cm³ of tetrahydrofuran iscooled to -10° C., and 4.89 cm³ of a 1.6M solution of N-butyllithium inn-hexane is added, operating at a temperature lower than 5° C. Afteragitation for 20 minutes, the mixture is cooled to -25° C., and drop bydrop poured into a solution of 2 g of diethylaminobenzenesulphonylchloride in 15 cm³ of tetrahydrofuran, maintaining the temperature lowerthan -20° C. The whole is left to return to ambient temperature andagitated for 2 hours. The solvent is eliminated under reduced pressureand the residue is chromatographed on silica (eluent: ethylacetate-n-hexane 1-1). The residue is taken up in isopropyl ether and0.74 of expected product is obtained.

m.p.=128°-130° C.

Analysis: C₁₄ H₂₀ N₂ O₃ S: 296.392: Calculated: C % 56.73, H % 6.8, N %9.45. Found: C% 56.59, H% 6.73, N% 9.38.

The 4-(diethylamino)-benzenesulphonyl chloride used at the start of theexample was prepared as follows:

24.84 g of 4-diethylaminobenzenesulphonic acid [Liebigs Ann. Chem.(1982) 282] and 22.56 g of phosphorus pentachloride are mixed togetherin 350 cm³ of methylene chloride and heated to reflux for 4 hours. Themixture is cooled to ambient temperature, the solvent is evaporated offunder reduced pressure, the residue is taken up with toluene, filteredon celite and concentrated to dryness under reduced pressure. 20.39 g ofexpected product is obtained.

EXAMPLE 3 1-[4-(dimethylamino)benzenesulphonyl]-2-pyrrolidinone

3.44 g of sodium hydride (at 55-60% in oil) is added to a solutioncomprising 6.11 g of 2-pyrrolidinone and 200 cm³ of dioxan, withagitation for one hour at ambient temperature. 15.76 cm³ of4-dimethylaminobenzenesulphonyl chloride [Beritche 43, 3038 (1910)] insolution in 250 cm³ of dioxan is added drop by drop, with agitation forone hour at ambient temperature. The sodium chloride is filtered off oncelite, the dioxan is evaporated off under reduced pressure, the residueis crystallized from acetone and 3.90 g of expected product is obtained.

m.p.=202°-204° C.

Analysis: C₁₂ H₁₆ N₂ O₃ S: 268.340: Calculated: C % 53.71, H % 6.01, N %10.44. Found: C % 53.92, H % 5.97, N % 10.50. (Soluble in chloroform;slightly soluble in acetone, benzene and alcohol at 95°; insoluble inethyl ether, water, 2N hydrochloric acid and 2N sodium hydroxide.)

EXAMPLE 4 1-[4-(methylthio)benzenesulphonyl]-2-pyrrolidinone

16.95 cm³ of a 1.6M solution of n-butyllithium in n-hexane is added dropby drop to 2.29 g of 2-pyrrolidinone in solution in 160 cm³ of anhydroustetrahydrofuran cooled to -30° C., maintaining the temperature at -30°C. After agitation for 30 minutes, the mixture is poured drop by dropinto a solution containing 6 g of 4-methylthio-benzenesulphonyl chloride[J. Chem. Soc. (1948) 604] in 10 cm³ of tetrahydrofuran, operatingbetween -30° and -25° C. The whole is left to return to ambienttemperature. The solvent is evaporated off under reduced pressure, theresidue is taken up in water and the solid is filtered off. Aftercrystallization from isopropanol, 3.80 g of expected product isobtained.

m.p.=123°-125° C.

Analysis: C₁₁ H₁₃ NO₃ S₂ : 271.36: Calculated: C % 48.69, H % 4.83, N %5.16. Found: C % 48.91, H % 4.69, N % 5.22.

EXAMPLE 5 1-(4-isopropyloxybenzenesulphonyl)-2-pyrrolidinone

9.6 cm³ of a 1.6M solution of n-butyllithium in hexane is added to 1.3 gof 2-pyrrolidinone in solution in 90 cm³ of tetrahydrofuran, cooled to-30° C., maintaining the temperature between -20° C. and -30° C. Afteragitation for one hour at -30° C., at this temperature 4 g of4-isopropyloxybenzenesulphonyl [Helv. Chim. Acta 39, 1579 (1956)] insolution in 6 cm³ of tetrahydrofuran is poured drop by drop into themixture. After agitation for one hour at -30° C., the whole is left toreturn to ambient temperature. The solvent is evaporated off underreduced pressure and the residue is chromatographed on silica (eluent:cyclohexane-ethyl acetate 7-3). After crystallization from isopropanol,1.5 g of expected product is obtained.

m.p.=88°-90° C.

Analysis: C₁₃ H₁₇ NO₄ S: 283.35: Calculated: C % 55.10, H % 6.05, N %4.94. Found: C % 55.07, H % 5.98, N % 4.90.

EXAMPLE 6 1-[4-(methylsulphinyl)benzenesulphonyl]-2-pyrrolidinone

A solution containing 2.41 g of m-chloroperbenzoic acid in 48 cm³ ofmethylene chloride is added to 3.4 g of1-(4-methylthiobenzene-sulphonyl)pyrrolidin-2-one prepared as in Example4 in solution in 34 cm³ of methylene chloride, at a temperature notexceeding 25° C. After agitation at ambient temperature for 30 minutes,the reaction medium is then treated with a 10% aqueous solution ofsodium sulphite. The organic phase is separated off, washed with a 5%aqueous solution of sodium bicarbonate, then with water. After drying,the solvent is evaporated off under reduced pressure, and the residue iscrystallized from 95% ethanol. 1.70 g of expected product is obtained.

m.p.=127°-129° C.

Analysis: C₁₁ H₁₃ NO₄ S₂ : 287.36: Calculated: C % 45.98, H % 4.56, N %4.87. Found: C % 45.87, H % 4.60, N % 4.81.

EXAMPLE 7 1-(3-methoxybenzenesulphonyl)-2-pyrrolidinone

15.75 cm³ of a 1.6M solution of M-butyllithium in hexane is added to2.22 g of 2-pyrrolidinone in solution in 80 cm³ of tetrahydrofuran andcooled to -25° C., the temperature being maintained between -25° C. and-20° C. After agitation for 30 minutes at -25° C., a solution of 5.40 gof 3-methoxybenzenesulphonyl sulphonyl chloride [J. Chem. Soc. P.T.2.,579 (1982)] in 40 cm³ of tetrahydrofuran is poured drop by drop into themixture, operating between -25° C. and -20° C. After agitation for 30minutes at -25° C., the whole is allowed to return to ambienttemperature. The solvent is evaporated under reduced pressure; theresidue is taken up in water, filtered and crystallized fromisopropanol. 3.5 g of expected product is obtained.

m.p.=108°-109° C.

Analysis: C₁₁ H₁₃ NO₄ S: 255.298: Calculated: C % 51.75, H % 5.13, N %5.49. Found: C % 51.84, H % 5.12, N % 5.54.

EXAMPLE 8 1-(2-naphthylsulphonyl)-2-pyrrolidinone

15.6 cm³ of a 1.6M solution of butyllithium in hexane is added to 2.13 gof 2-pyrrolidinone in solution in 80 cm³ of tetrahydrofuran, cooled to-10° C., maintaining the temperature between -5° C. and +5° C. Afteragitation at -5° C. for 25 minutes, 6.12 g of beta-naphthalene-sulphonylchloride is added, without exceeding 0° C. The whole is then left toreturn to ambient temperature. The solvent is evaporated off underreduced pressure, the residue is taken up in ethyl acetate, and thelithium chloride is filtered off and after evaporating under reducedpressure, the residue is taken up in water and filtered. Finally aftercrystallization from isopropanol, 4 g of expected product is obtained.

m.p.=118°-120° C.

Analysis: C₁₄ H₁₃ NO₃ S: 275.3. Calculated: C % 61.07, H % 4.76, N %5.09. Found: C % 60.91, H % 4.72, N % 4.99.

Example 9 1-[(4-pyrrolidinyl)phenylsulphonyl]-2-pyrrolidinone Stage A4-(4-pyrrolidinylphenylsulphonylamino)butyric acid

4.9 g of 4-pyrrolidinebenzenesulphoyl chloride (Chem. Abst. 46, 8647 F),is added to a solution comprising 2.06 g of 4-aminobutyric acid and 2.4g of sodium hydroxide in 40 cm³ of water, then 50 cm³ of tetrahydrofuranis added in order to obtain a perfect solution. After agitation for 24hours at ambient temperature, followed by acidifying with acetic acid,the solvent is evaporated off at ambient temperature. After extractionwith chloroform, the organic phase is dried on sodium sulphate, filteredand evaporated to dryness. 2.4 g of expected product is obtained.

m.p.=161°-163° C.

Analysis: C₁₄ H₂₀ N₂ O₄ S: 312.39 Calculated: C % 53.83, H % 6.45, N %8.97. Found: C % 53.16, H % 6.25, N % 8.72.

Stage B 1-[(4-pyrrolidinyl)phenylsulphonyl]-2-pyrrolidinone.

2.5 g of product prepared as in stage A and 2.5 g of sodium acetate areheated for 4 hours at reflux in 50 cm³ of acetic anhydride, followed bycooling and evaporating to dryness. The residue is taken up in 150 cm³of benzene, heated to reflux and filtered on active charcoal. Byaddition of n-hexane, a precipitate is obtained which is filtered offand washed with hexane. 1.7 g of expected product is obtained.

m.p.=235°-237° C.

Analysis: C₁₄ H₁₈ N₂ O₃ S: 294.38. Calculated: C % 57.12, H % 6.16, N %9.51. Found: C % 56.77, H % 6.24, N % 9.31.

EXAMPLE 10 1-[4-(1-piperidinyl)phenylsulphonyl]-2-pyrrolidinone Stage A4-(4-piperidinephenylsulphonylamino)butyric acid

1 g of 4-piperidinebenzenesulphonyl chloride is added to a solutioncomprising 0.39 g of 4-aminobutyric acid, 0.462 g of sodium hydroxide insolution in 10 cm³ of water, then 5 cm³ of tetrahydrofuran is added soas to obtain a solution. The solution is agitated for 24 hours atambient temperature, then acidified with acetic acid. The solvent isevaporated off, the organic phase is extracted with chloroform, dried onsodium sulphate, filtered and evaporated to dryness. Aftercrystallization from ethyl acetate, 0.5 g of expected product isobtained.

m.p.=130°-132° C.

Analysis: C₁₅ H₂₂ N₂ O₄ S: 326.43: Calculated: C % 55.19, H % 6.79, N %8.58. Found: C % 54.69, H % 6.72, N % 8.37.

Stage B 1-[4-(1-piperidinyl)phenylsulphonyl]-2-pyrrolidinone

A mixture made up of 3 g of product obtained as in stage A and 3 g ofsodium acetate in 60 cm³ of acetic anhydride is taken to reflux for 3hours, then cooled to ambient temperature and evaporated to dryness.After extraction with chloroform and with water, the organic phase isseparated, dried on sodium sulphate, filtered and evaporated. 2.5 g ofexpected product is obtained.

m.p.=168°-170° C.

After crystallization from isopropanol, 1.80 g of product is obtained.

m.p.=170°-172° C.

Analysis: C₁₅ H₂₀ N₂ O₃ S: 308.41; Calculated: C % 58.42, H % 6.54, N %9.08. Found: C % 58.31, H % 6.46, N % 8.89.

The 4-piperidinebenzenesulphonyl chloride used at the start of Example10 was prepared as follows.

9.3 g of dioxan is added to a solution comprising 8.46 g of sulphuricanhydride in 45 cm³ of methylene chloride, cooled to 0° C./+5° C., then,at the same temperature, 17.1 g of N-phenylpiperidine in solution in 45cm³ of methylene chloride is added. The mixture is left to return toambient temperature, then heated to reflux for one hour. Afterevaporation to dryness, the residue is taken up by a 10% solution ofsodium carbonate. The aqueous phase is washed with benezene andconcentrated; the residue is dried and treated with 200 cm³ ofphosphorus oxychloride and 21.8 g of phosphorus pentachloride for 12hours at ambient temperature. After evaporation to dryness, the residueis taken up with chloroform and water, the organic phase is separated,dried on sodium sulphate, filtered and evaporated to dryness. 19 g ofproduct is obtained which is used just as it is.

EXAMPLE 11 1-[(4-morpholino)phenylsulphonyl]-2-pyrrolidinone Stage A(4-morpholinophenylsulphonylamino)butyric acid

10 g of 4-morpholinobenzenesulphonyl chloride is added to a solutioncomprising 3.94 g of 4-amino butyric acid and 4.6 g of sodium hydroxidein 80 cm³ of water, then 70 cm³ of tetrahydrofuran is added so as toobtain a solution. The temperature increases from 20° to 27° C. Thesolution is allowed to return to ambient temperature and maintainedunder agitation for 24 hours, after which it is acidified with aceticacid, and the solvent is evaporated under reduced pressure. The residueis taken up with 50 cm³ of distilled water; the precipitate is filteredoff, washed with water, dried and 7.6 g of expected product is obtained,m.p.=163°-165° C., which is recrystallized from ethyl acetate.

m.p.=167°-168° C.

Analysis: C₁₄ H₂₀ N₂ O₅ S: 328.39 Calculated: C % 51.20, H % 6.14, N %8.53. Found: C % 51.21, H % 6.07, N % 8.61.

Stage B 1-[(4-morpholino-phenylsulphonyl]-2-pyrrolidinone

6.2 g of product obtained in Stage A, 6.2 g of sodium acetate and 124cm³ of acetic anhydride are heated to reflux for 4 hours. After coolingto ambient temperature and evaporating to dryness, the residue is takenup with 50 cm³ of water, filtered, washed with 10 cm³ of water anddried. 5.65 g of expected product is obtained.

m.p.=208°-210° C. After recrystallization from acetone, 4.3 g of productis obtained, melting at 210°-211° C.

Analysis: C₁₄ H₁₈ N₂ O₄ S: 310.38: Calculated: C % 54.17, H % 5.85, N %9.03. Found: C % 54.30, H % 5.91, N % 8.92.

The 4-morpholinobenzenesulphonyl chloride used at the start of Example11 was prepared as follows.

9.68 g of dioxane, then 17.95 g of N-phenylmorpholine dissolved in 30cm³ of methylene chloride are added drop by drop to a solutioncomprising 8.8 g of sulphuric anhydride in 100 cm³ of methylene chloridecooled to between -5° C. and +3° C., without the temperature exceeding+5° C. The whole is left to return to ambient temperature, then heatedto reflux for one hour and a half. After cooling to ambient temperature,and extracting with water, the aqueous phase is neutralized with sodiumcarbonate, evaporated to dryness and the residue is dried under reducedpressure at 90° C. for 4 hours. 19.5 g of sodium salt is obtained whichis treated with 21 g of phosphorus pentachloride in 100 cm³ of methylenechloride, heating to reflux for 4 hours. After cooling to ambienttemperature and evaporating to dryness, the residue is taken up inbenzene with a little water. The organic phase is separated, dried onsodium sulphate, filtered and the solvent is evaporated off. 11.5 g ofexpected product is obtained. m.p.=105°-108° C. After crystallizationfrom benzene, the product is obtained, melting at 120°-122° C.

Analysis: C₁₀ H₁₂ ClNO₃ S: 261.77 Calculated: C % 45.88, H % 4.62, N %5.35 Found: C % 45.67, H % 4.59, N % 5.44.

EXAMPLE 12 1-[(4-cyclopentyl)phenylsulphonyl]-2-pyrrolidinone

8 cm³ of a 1.5M solution of n-butyllithium in n-hexane is poured into asolution comprising 1.02 g, or 0.9 cm³, of 2-pyrrolidinone in 50 cm³ oftetrahydrofuran, cooled to -70° C., without the temperature exceeding-60° C. After 15 minutes, 3 g of benzenesulphonyl-4-cyclopentyl chloridein solution in 12 cm³ of tetrahydrofuran is added, maintaining thetemperature between -65° and -70° C. After allowing to return to ambienttemperature over 2 hours and evaporating to dryness, the residue ischromatographed on silica (eluent:ethyl acetate-n-hexane 1-3) and 2.6 gof expected product is obtained. m.p.=105°-106° C., which aftercrystallization from isopropanol gives 2 g of product melting at105°-106° C.

Analysis: C₁₅ H₁₉ NO₃ S: 293.40: Calculated: C % 61.41, H % 6.53, N %4.77. Found: C % 61.22, H % 6.71, N % 5.06.

The benzenesulphonyl-4-cyclopentyl chloride used at the start of Example12 was prepared as follows.

14.7 g, or 12 cm³, of trimethylsilyl chlorosulphonate is added to 11.5 gof phenylcyclopentane [Chem. Abstr. 51, 7317c (1957)], at between +5° C.and +10° C. The mixture is allowed to return to ambient temperature andagitated for 2 hours. After evaporation to dryness, the residue isdissolved in 100 cm³ of chloroform, treated with 7.5 g of phosphoruspentachloride and heated for 2 hours at reflux. After evaporating todryness, the oily residue is chromatographed on silica (eluent: ethylacetate-n-hexane 1-3) and 3.3 g of expected product is obtained.

m.p.=48°-50° C.

EXAMPLE 13 1-[(4-cyclohexyl)phenylsulphonyl]-2-pyrrolidinone

The operation is carried out as in Example 12, using 1.97 g of2-pyrrolidinone in 100 cm³ of tetrahydrofuran, 15.5 cm³ of a 1.5Msolution of n-butyllithium in hexane, and 6 g of(4-cyclohexyl)benzene-sulphonyl chloride [J. Am. Chem. Soc. 62, 513(1940)] in 24 cm³ of tetrahydrofuran. 3 g of expected product isobtained.

m.p.=91°-92° C. After crystallization from isopropanol, 2 g of productis obtained.

m.p.=91°-92° C.

Analysis: C₁₆ N₂₁ NO₃ S: 307.42: Calculated: C % 62.51, H % 6.88, N %4.56. Found: C % 62.29, H % 6.74, N % 4.69.

EXAMPLE 14 1[(4-dipropylamine)phenylsulphonyl]-2-pyrrolidinone

The operation is carried out as in Example 12, using 1.39 g of2-pyrrolidinone in 42 cm³ of tetrahydrofuran, 10.8 cm³ of a 1.5Msolution of n-butyllithium in n-hexane, then at between -20° C. and -10°C., 4.5 g of (4-dipropylamino)benzenesulphonyl in 25 cm³ oftetrahydrofuran is added. 2 g of expected product is obtained.

m.p.=88°-90° C. After crystallization from isopropanol, 1.5 g of productis obtained, melting at 92°-93° C.

Analysis: C₁₆ H₂₄ N₂ O₃ S: 324.454: Calculated: C % 59.23, H % 7.46, N %8.63. Found: C % 59.13, H % 7.53, N % 8.44.

The (4-dipropylamino)benzenesulphonyl chloride used at the start ofExample 14 was prepared as follows:

10.2 g of (N,N-dipropylaniline) (Annalen der Chemie 214, 168) is addedto a solution cooled to +5° C./+10° C. comprising 10.86 g (or 8.86 cm³)of trimethylsilyl chlorosulphonate and 50 cm³ of methylene chloride. Themixture is allowed to return to ambient temperature and evaporated todryness. The residue is taken up in acetone, filtered and dried and 4.9g of acid is obtained, to which is added 100 cm³ of methylene chlorideand 2.63 g of phosphorus pentachloride, heating to reflux for 4 hours.After cooling to ambient temperature and evaporating to dryness, theoily residue is taken up with benzene and water. The organic phase isseparated, dried on sodium sulphate, filtered and evaporated to dryness.4.5 g of expected product is obtained which is used just as it is.

EXAMPLE 15 1-[(4-dibutylamino)phenylsulphonyl]-2-pyrrolidinone

The operation is carried out as in Example 12, using 1.76 g of2-pyrrolidinone in 51 cm³ of tetrahydrofuran, 13.8 cm³ of a 1.5Msolution of n-butyllithium in n-hexane at a temperature between -20° C.and -15° C., then 6.3 g of 4-dibutylaminobenzenesulphonyl chloride in 35cm³ of tetrahydrofuran is added. After chromatography on silica (eluent:ethylacetate-n-hexane 1-1) and crystallization from isopropanol, 3 g ofexpected product is obtained.

m.p.=73°-74° C.

Analysis: C₁₈ H₂₈ N₂ O₃ S: 352.51; Calculated: C % 61.33, H % 8.01, N %7.95. Found: C % 61.14, H % 8.03, N % 7.86.

The 4-dibutylaminobenzenesulphonyl chloride used at the start of Example15 was prepared as follows.

The operation is carried out as indicated for the preparation of thestarting product of Example 14, using 10 g of (N,N-dibutylaniline) [J.Chem. Soc. (1956), 3293], and 9.19 g (or 7.5 cm³) of trimethysilylchlorosulphonate in 50 cm³ of methylene chloride. After evaporation todryness, the residue is taken up in 100 cm³ of methylene chloride, then10.1 g of phosphorus pentachloride is added, heating to reflux for anhour and a half. After cooling and evaporation to dryness, the residueis taken up in water and extracted with chloroform. The extracts aredried on sodium sulphate, filtered, and evaporated to dryness. Theresidue is chromatographed on silica (eluent: ethyl acetate-n-hexane1-1) and 6.3 g of expected product is obtained which is used just as itis.

EXAMPLE 16 1-[(4-diisopropylamino)phenylsulphonyl]-2-pyrrolidinone

The operation is carried out as in Example 12 using 2.76 g of2-pyrrolidinone in 81 cm³ of tetrahydrofuran, 21.7 cm³ of a 1.5Msolution of n-butyllithium in n-hexane at a temperature between -20° C.and -15° C., then 9 g of (4-diisopropylamino)benzenesulphonyl chloridein 45 cm³ of tetrahydrofuran. After chromatography (eluent: ethylacetate-n-hexane 1-2), 3.4 g of expected product is obtained.

m.p.=140°-145° C., then 142°-145° C. after crystallization fromisopropanol.

Analysis: C₁₆ H₂₄ N₂ O₃ : 324.45: Calculated: C % 59.23, H % 7.46, N %8.63. Found: C % 59.09, H % 7.38, N % 8.57.

The 4-diisopropylaminobenzenesulphonyl chloride used at the start ofExample 16 was prepared as follows.

The operation is carried out as indicated for the preparation of thestarting product of Example 14, using 13 g of (N,N-diisopropyl-aniline)[J. Org. Chem. 22, 832 (1957)], and 14 g (or 11.43 cm³) oftrimethylsilyl chlorosulphonate in 50 cm³ of methylene chloride. Afterevaporation to dryness, the residue is taken up in 100 cm³ of methylenechloride, 14 g of phosphorus pentachloride is added and the whole istaken to boiling point for 4 hours. After evaporation to dryness, theresidue is taken up in 50 cm³ of water, and extraction is carried outwith ether. The extracts are dried on sodium sulphate, filtered andevaporated. 9.6 g of expected product is obtained, which is used just asit is.

EXAMPLE 17 1-(4-isopropylthiophenylsulphonyl)-2-pyrrolidinone

The operation is carried out as in Example 12, using 1.7 g of2-pyrrolidinone in 61 cm³ of tetrahydrofuran, 13.3 cm³ of a 1.5Msolution of n-butyllithium in n-hexane and 5 g of4-isopropylsulphidebenzenesulphonyl chloride in 5 cm³ oftetrahydrofuran. The mixture is left to return to ambient temperatureand evaporated to dryness. The residue is taken up in water, and theprecipitate is filtered and dried. 3.1 g of expected product isobtained.

m.p.=62°-66° C., which is recrystallized from isopropanol, and 2.4 g ofproduct is recovered, melting at 68°-70° C.

Analysis: C₁₃ H₁₇ NO₃ S₂ : Calculated: C % 52.15, H % 5.72, N % 4.68.Found: C % 51.86, H % 5.63, N % 4.57.

The 4-isopropylsulphidebenzenesulphonyl chloride used at the start ofExample 17 was prepared as follows.

5.8 g of dioxan is added drop by drop, at a temperature between -5° C.and +3° C., to a solution comprising 5.32 g of sulphuric anhydride(Coll. Org. Synth. IV, p. 846) in 24 cm³ of 1,2-dichloroethane, then 10g of isopropylphenyl sulphide [J. Chem. Soc. (1948), 1820] dissolved in20 cm³ of 1,2-dichloroethane, without the temperature exceeding +5° C.The whole is left to return to ambient temperature over one hour, thenheated to reflux for one hour and a half. After evaporation to dryness,the residue is dissolved in 50 cm³ of water, neutralized with sodiumbicarbonate in solution at 10%, filtered and dried. 15 g of sodium saltis obtained which is treated with 150 cm³ of methylene chloride and11.55 g of phosphorus pentachloride, heating to reflux for 2 hours.After leaving to cool to ambient temperature, filtering and evaporatingthe solvent, 5 g of pure product is obtained.

EXAMPLE 18 1-[4-(4-hexahydroazepin)phenylsulphonyl]-2-pyrrolidinoneStage A 4-(4-hexahydroazepinephenylsulphonylamino) butyric acid

6 g of 4-hexahydroazepinebenzenesulphonyl chloride is added to asolution comprising 2.26 g of 4-aminobutyric acid and 2.6 g of sodiumhydroxyde in solution in 60 cm³ of water, then 60 cm³ of tetrahydrofuranis added so as to obtain a solution. After agitation for 3 hours atambient temperature, the solvent is evaporated off, the remainder isacidified with acetic acid, diluted with 100 cm³ of water, and theprecipitate is filtered off and dried. 3.8 g of expected product isobtained.

m.p.=133°-135° C. After crystallization from an ethanol-water mixture(1-1), m.p.=134°-135° C.

Analysis: C₁₆ H₂₄ N₂ O₄ S: 340.454; Calculated: C % 56.45, H % 7.10, N %8.23. Found: C % 54.55, H % 7.12, N % 8.22.

Stage B 1-[4-(4-hexahydroazepin)phenylsulphonyl]-2-pyrrolidinone

A mixture comprising 3.5 g of product obtained in Stage A and 3.5 g ofsodium acetate in 35 cm³ of acetic anhydride is taken to reflux for onehour. The mixture is cooled to ambient temperature and evaporated todryness. The residue is taken up in 30 cm³ of water, filtered off anddried. 3 g of product is obtained which is chromatographed on silica(eluent:ethyl acetate). After crystallization from an isopropanol-watermixture (1-1), 2 g of product is obtained.

m.p.=155°-156° C.

Analysis: C₁₆ H₂₂ N₂ O₃ S: 322.438; Calculated: C % 59.60, H % 6.88, N %8.69. Found: C % 59.66, H % 6.94, N % 8.66.

The 4-hexahydroazepinebenzenesulphonyl chloride used at the start ofExample 18 was prepared as follows:

2.9 g of dioxane is added to a solution comprising 2.64 g of sulphuricanhydride in 78 cm³ of methylene chloride cooled to +5° C./+10° C., thenat the same temperature 5.26 g of 1-phenylhexahydroazepine in solutionin 53 cm³ of methylene chloride is added. The mixture is allowed toreturn to ambient temperature, then heated to reflux for 2 hours. Aftercooling again to ambient temperature, 200 cm³ of ethyl ether is added,the precipitate is filtered off, washed with ether and dried and 7.2 gof acid is obtained, melting at 235° C. (decomp.). This acid is treatedwith 36 cm³ of phosphorus oxychloride, 36 cm³ of methylene chloride and5.87 g of phosphorus pentachloride for 4 hours at ambient temperature.After evaporation to dryness, the residue is taken up with chloroformand with water; the organic phase is separated, dried on sodiumsulphate, filtered and evaporated to dryness. 6.6 g of product isobtained which is used just as it is.

m.p.=85°-88° C.

EXAMPLE 19 1-[(4-piperazino)phenylsulphonyl]-2-pyrrolidinone Stage A4-[4-(4-benzyloxycarbonylpiperazin-1-yl)phenylsulphonylamino] butyricacid

10.5 g of 4-[(4-benzyloxycarbonyl)piperazin-1-yl] benzenesulphonylchloride is added to a solution comprising 2.7 g of 4-amino butyric acidand 3.18 g of sodium hydroxyde in 50 cm³ of water, then 70 cm³ oftetrahydrofuran is added so as to obtain a solution. The solution isagitated for one hour at ambient temperature, the solvent is evaporatedoff, the remainder is acidified with acetic acid, then extracted withchloroform. The organic phase is dried on sodium sulphate, filtered offand evaporated to dryness. 8.2 g of expected product is obtained.

Stage B 1-[(4-piperazino)phenylsulphonyl]-2-pyrrolidinone

8.2 g of product obtained in Stage A, 8.2 g of sodium acetate and 123cm³ of acetic anhydride are heated to reflux for 30 minutes. The mixtureis cooled to ambient temperature, evaporated to dryness, the residue istaken up with 100 cm³ of water, filtered and dried. 5.6 g of1-[4-(4-benzyloxycarbonylpiperazin-1-yl)phenylsulphonyl]-2-pyrrolidinoneis obtained. m.p.=153°-155° C. After recrystallization from anethanol-acetone mixture (10-1), 3.7 g of product is obtained, melting at158°-160° C. 7 g of product prepared as above and 1 g of palladium areput in suspension in 105 cm³ of dimethylacetamide, a few drops oftriethylamine are added, then the whole is hydrogenated under ambientpressure (with 280 cm³ of hydrogen). The catalyst is filtered off,evaporated to dryness and 2 g of product is obtained which is dissolvedin acetic acid and evaporated to dryness. The residue is taken up inisopropyl alcohol and 1.5 g of crystallized product is obtained.

m.p.=108° C.

Analysis: C₁₄ H₁₉ N₃ O₃ S, CH₃ COOH, 0.5 H₂ O: 378.46: Calculated: C %50.78, H % 6.39, N % 11.10. Found: C % 50.39, H % 6.15, N % 11.14.

The 4-[(4-benzyloxycarbonyl)piperazin-1-yl] benzenesulphonyl chlorideused at the start of Example 19 was prepared as follows:

Stage A 4-carbobenzyloxy 1-phenylpiperazine

A solution of 4.4 g of benzyl chloroformate in toluene is added to asolution comprising 4.05 g of N-phenylpiperazine in 50 cm³ of benzeneand 2.5 g of triethylamine, at a temperature between +5° C. and +10° C.The whole is allowed to return to ambient temperature and agitated for 2hours. The triethylamine chloride is filtered off and evaporated todryness. An oily residue is obtained which is solidified in n-hexane and7.1 g of expected product is recovered. m.p.=49°-51° C. Afterrecrystallization from an ethyl ether -n-hexane mixture, m.p.=51°-52° C.

Analysis: C₁₈ H₂₀ N₂ O₂ : 296.37. Calculated: C % 72.95, H % 6.80, N %9.45. Found: C % 73.13, H % 6.79, N % 9.38.

Stage B 4-[(4-benzyloxycarbonyl)piperazin-1-yl] benzenesulphonylchloride

A solution comprising 3.04 g of sulphuric anhydride in 90 cm³ ofmethylene chloride is added to 11 g of product obtained in Stage A insolution in 100 cm³ methylene chloride, then 3.6 g of dioxan is added,at a temperature between +5° C. and +10° C. The whole is allowed toreturn to ambient temperature, then heated to reflux for 2 hours,followed by cooling to ambient temperature, diluting with 300 cm³ ofethyl ether, filtering and drying. 13.7 g of product is obtained,melting at 210° C., which is treated with 100 cm³ of phosphorusoxychloride and 7.57 g of phosphorus pentachloride for 4 hours atambient temperature. After evaporation to dryness, the residue is takenup with chloroform and with water, the organic phase is separated, driedon sodium sulphate, filtered off and evaporated to dryness. 10.6 g ofproduct is obtained which is used just as it is.

EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

a) Tablets were prepared corresponding to the following formula:

Product of Example 1: 10 mg

Excipient q.s. for a tablet completed at: 300 mg

(Detail of excipient: lactose, wheat starch, treated starch, ricestarch, magnesium stearate, talc.)

b) Gelules were prepared corresponding to the following formula:

Product of Example 1: 20 mg

Excipient g.s. for a gelule completed at: 300 mg

(Detail of excipient: talc, magnesium stearate, aerosil.)

BIOCHEMICAL AND PHARMACEUTICAL STUDIES

1) Bonding with the various cerebral receptors

The results obtained by two significant examples of the invention areshown in the following table.

a) Muscarine receptor 1

This is prepared from cortex removed from the brains of a male ratweighing 150 to 200 g, (Iffa Credo) pulverized with Polytron in a bufferNa/K 10 mM pH 7.4. After incubation (aliquots of 0.5 ml of homogenate)for 60 minutes at 25° C. in the presence of 0.25 nM of ³ H pirenzepine,either alone, or with the product under test, or with an excess ofpirenzepine at 10⁻⁵ M (in order to determine the non-specificradioactivity fixed), the incubates are cooled and filtered.

The filtration is carried out on Whatman GF/C filters prewashed in asolution of polyethylene-imine at 0.05%. The filters are rinsed with 3×5ml of phosphate Na/K buffer 10 mM pH 7.4, then measurements are made byliquid scintillation.

b) Muscarine receptor 2

The preparation is made from the brains of a male rat weighing 150 to200 g (Iffa Credo).

The brains are pulverized (Teflon-glass) in a 0.32M solution of sucrose.The homogenate is centrifuged for 10 minutes at 1000 g (0°-4° C.).

The supernatant obtained is recovered and centrifuged at 30,000 g for 15minutes (0°-4° C.).

The deposit is put in suspension in a buffer Tris 50 mM pH 7.5 and thenew homogenate is centrifuged again at 30,000 g for 15 minutes (0°-4°C.).

The deposits after elimination of the supernatant, can be usedstraight-away or kept for up to one month at -30° C.

For one experiment the deposits are first of all thawed out, ifnecessary, to ambient temperature and put in suspension, using a Dounce,in a buffer Tris 50 mM pH 7.5. Aliquots of 2 ml are incubated for 60minutes at 25° C. in the presence of 0.3 nM of ³ H quinuclidinylbenzylate either alone, or with the product under test, or withbenzatropine at 10⁻⁵ M in order to determine the non-specificradioactivity fixed.

At the end of the incubation the incubate tubes are cooled to 4° C. andfiltered rapidly on Whatman GF/C filters. The filters are rinsed with3×5 ml of buffer Tris 50 mM pH 7.5, then measurements are made by liquidscintillation [Henry I Yamamura, Solomon H. Snyder, Proc. Nat. Acad. Sc.(1974) 71 No. 5, 1725-1729].

The results are expressed in IC₅₀ (concentration necessary forinhibiting by 50% the specific radioactivity fixed.)

                  TABLE 1                                                         ______________________________________                                                Affinity for muscarine receptors M.sub.1 and M.sub.2                  Compound of               /.sup.3 H/Quinuclidinyl                             Example   /.sup.3 H/Pirenzepine                                                                         benzylate                                           ______________________________________                                        1         130             1300                                                2         98              1300                                                ______________________________________                                    

The compounds of examples 1 and 2 show a remarkable and useful affinityfor the muscarine receptor, and mainly for the M₁ type receptor. Bycontrast the same compounds showed a negligible affinity (IC₅₀5000-10,000) for the other receptors examined, among which there can becited those of dopamine, of serotonine (5 HT₁ and 5 HT₂), ofbenzodiazepines, of GABA, adrenoreceptors (alpha 1, alpha 2, beta 1,beta 2) or even opiated receptors (mu, kappa).

2) Interaction and affinity with various intestinal receptors

The interaction of the compounds with various receptors was evaluated onthe isolated ileum of a guinea-pig according to the following method.

Segments of the ileum of guinea-pigs of 2.5-3 cm were washed andimmediately suspended in a bath containing 10 ml of Tyrode's solution at37° C. and aerated with a mixture of oxygen (95%) and carbon dioxide(5%). After a stabilization period of at least 30 minutes contractionswere recorded, while the preparation was maintained under constanttension of 1 g, by means of a detector connected to a polygraph. Theagonistic action was evaluated by leaving the compound in contact withthe isolated tissue for a period necessary to show the maximumconcentration; then it was washed with the Tyrode's solution. Thefollowing dose was added only after the preparation had returned to itsbase line. Arecoline was used as a reference product. The antagonistaction was evaluated on the contractions induced by acetylcholine(1×10⁻⁶ M), histamine (1 ×10⁻⁵ M), serotonine (1×10⁻⁶ M) and bariumchloride (2×10⁻⁴ M). Atropine diphenyldramine, methysergide andpapaverine were used as reference products. The contact time beforeadding the agonist was one minute.

For each compound the dose response curves are obtained with 4 to 6different concentrations and 3 to 5 independent tests. The agonistactivity is expressed by pD₂ (negative logarithm of the dose whichproduces 50% of the maximum effect). The antagonist activity isexpressed by IC₅₀ (concentration inhibiting the maximum response by50%). The results obtained with the compounds of examples 1 and 2 areshown in the following table:

                                      TABLE 2                                     __________________________________________________________________________            Antagonism with various agents                                                                        Agonist                                       Compound of                                                                           (IC.sub.50 :M)          Action                                        Example Ach.  Istam.                                                                              Seroton.                                                                            BaCL.sub.2                                                                          (pD.sub.2)                                    __________________________________________________________________________    1       6.4 × 10.sup.-8                                                               >10.sup.-4                                                                          >10.sup.-4                                                                          1.6 × 10.sup.-5                                                               <4                                            2       6.2 × 10.sup.-8                                                               >10.sup.-4                                                                          >10.sup.-4                                                                          6.0 × 10.sup.-6                                                               <4                                            Atropine                                                                              9.5 × 10.sup.-9                                                 Diphenyl-     8.3 × 10.sup.-7                                           dramine                                                                       Methysergide        1.1. × 10.sup.-7                                    Papaverine                4.5 × 10.sup.-5                               Arecoline                       6.68                                          __________________________________________________________________________

The "in vitro" studies on the isolated ileum of guinea-pigs revealedthat the compounds of the invention are powerful antimuscarin agents.They antagonize the contractions induced by acetylcholine but not thoseinduced by histamine and serotonine. These compounds showed anantagonist activity slightly lower (approx. 7 times) than that ofatropine.

The remarkable antagonist action of the compounds of the invention wasconfirmed on the isolated colon of rats. In this test it was establishedwhether the antagonist activity was of competitive or non-competitivetype.

The following method was used: segments of the colon of rats of about2.5 cm are washed and suspended in an insulated bath containing 10 ml ofa solution of De Jalon having the following composition: (mM): NaCl 154;KCl 5.7; CaCl₂ 0.27; NaHCO₃ 5.9 and glucose 2.5. The temperature of thebath is maintained at 32° C. In these conditions, while maintaining thepreparation under a tension of 1 g, the spontaneous activity of thecolon is minimal. After a stabilization period of at least 30 minutes,the tension variations are recorded using an isometric transducerconnected to a recorder. A series of tests was carried out to evaluatethe antagonist activity in relation to the contractions induced by amaximum dose of acetylcholine. (3×10⁻⁶ M).

The compounds are left in contact with the preparation for 3 minutesbefore adding acetylcholine.

Atropine was used as a reference product. For each compound thedose-response curves are obtained with 4 to 6 different concentrationsand 3 to 5 independent tests.

The antagonist activity is expressed in IC₅₀ (concentration inhibitingthe maximum response induced by acetylcholine by 50%).

In a second series of tests the acetylcholine is added to the bath incumulative doses according to the van Rossum method (J. M. van Rossum,Arch, Int. Pharmacodyn. 143, 299, 1963). Having obtained two equal andconsecutive dose-response curves with acetylcholine, a thirddose-response curve is obtained in the presence of the compound (contacttime of compound before acetylcholine =5 min.) Each compound was testedwith 3-4 different concentrations.

The antagonist affinity and the type of antagonism (competitive,non-competitive) for the muscarine receptors was calculated according toSchild's method (H. D. Schild, Brit. J. Pharmacol. 2, 189, 1947).

                  TABLE 3                                                         ______________________________________                                        Compound of                                                                              Isolated colon of rat                                              Example    IC.sub.50     pA.sub.2                                                                             "Slope"                                       ______________________________________                                        1          2.8 × 10.sup.-7                                                                       7.77   0.89                                          2          1.6 × 10.sup.-7                                                                       7.35   1.08                                          Atropine   2.7 × 10.sup.-8                                                                       8.31   0.97                                          ______________________________________                                    

The two compounds of example 1 and 2, like atropine, gave a paralleldisplacement towards the right of the dose-response curve ofacetyl-choline without reducing the maximum contraction.

The slope of the regression lines in the "Schild plot" corresponds tothe theoretical value of 1 (tab. 3). According to this data and thevalues of pA₂ obtained (tab. 3) it can be concluded that the compoundsof the invention are competitive antagonists for muscarine receptors,involved in the contractions of the colon of a rat induced byacetylcholine, and they show a power which is about 4 to 10 timesinferior to that of atropine.

3) "In vivo" anticholinergic action

The anticholinergic activity of the compounds was determined byevaluating the capacity to inhibit cholinomimetic effects induced bycarbachol. Atropine sulphate was used as reference product.

CD₁ male mice are used weighing 25 to 30 g. They are divided into groupsof 5 animals and treated by intraperitoneal route, in scaled doses, withthe products or with 0.25% of Methocel for the controls. 10 animals areused for each dose. 30 minutes after the administration of thecompounds, the mice are subcutaneously injected with 1 mg/kg ofcarbachol, dissolved in physiological serum.

Each animal was examined 30 minutes after the injection of carbachol toevaluate the presence of diarrhea, salivation and watering of the eyes;the body temperature was also measured using a thermocouple inserted 1.5cm into the rectum.

The carbachol (1 mg/kg s.c.) induced diarrhea, salivation and wateringof the eyes in all the control mice and a decrease in rectal temperatureof about 2.5° C.

For each compound, there was determined, and recorded in the followingtable, the dose able to inhibit, in 50% of the animals, the appearanceof peripheral cholinomimetic symptoms induced by carbachol, and toincrease by 1° C. the hypothermic effect induced by the cholinergicagent.

                  TABLE 4                                                         ______________________________________                                        Dose mg/kg i.p.                                                               Compound                   Watering of                                                                            Body                                      of Example                                                                            Diarrhea Salivation                                                                              Eyes     Temperature                               ______________________________________                                        1       7        10        >50      50                                        2       7        >50       >50      >50                                       10      3        50        >50      >50                                       18      1        15        50       15                                        Atropine                                                                              0.04     0.06      0.05     0.03                                      ______________________________________                                    

The results obtained show that, in contrast to atropine, the compoundsof the examples, in particular those of examples 1, 2 and 10, exert "invivo" a selective anticholinergic action on the intestinal musculature.

What is claimed is:
 1. A method of treating a patient suffering frommuscle spasms comprising administering to the patient anantispasmodically effective amount of a compound of Formula (I)##STR11## in which R represents the radical ##STR12## in which R₁represents the radical ##STR13## in which R₂ and R₃ form together withthe nitrogen atom to which they are joined piperidyl, and apharmacologically acceptable carrier.
 2. A method according to claim 1wherein the compound of Formula (I) is1-[4-(1-piperidinyl)phenyl-sulphonyl]-2-pyrrolidinone.
 3. A therapeuticcomposition for the treatment of a patient suffering from muscle spasms,comprising an antispasmodically effective amount of a compound offormula (I) ##STR14## in which R represents the radical ##STR15## inwhich R₁ represents the radical ##STR16## in which R₂ and R₃ formtogether with the nitrogen atom to which they are joined piperidyl, anda pharmacologically acceptable carrier.
 4. A therapeutic compositionaccording to claim 3 wherein the compound of Formula (I) is1-[4-(1-piperidinyl)phenylsulphonyl]-2-pyrrolidinone.